Molecular genetics of prostate cancer: new prospects for old challenges

Abstract

Despite much recent progress, prostate cancer continues to represent a major cause of cancer-related mortality and morbidity in men. Since early studies on the role of the androgen receptor that led to the advent of androgen deprivation therapy in the 1940s, there has long been intensive interest in the basic mechanisms underlying prostate cancer initiation and progression, as well as the potential to target these processes for therapeutic intervention. Here, we present an overview of major themes in prostate cancer research, focusing on current knowledge of principal events in cancer initiation and progression. We discuss recent advances, including new insights into the mechanisms of castration resistance, identification of stem cells and tumor-initiating cells, and development of mouse models for preclinical evaluation of novel therapuetics. Overall, we highlight the tremendous research progress made in recent years, and underscore the challenges that lie ahead.

Organ-Specific Cancer Metabolism and Its Potential for Therapy

“…In addition, more attempts to develop drugs that act on other prostate cancer targets, such as ETS-fusions, or the PI3K signaling pathway, or fatty acid metabolism, are reported [117,118]. Prostate cancer originates in the peripheral zone of the prostate where about 70% of the cancer emerges in a multifocal manner [119]. Upon an inflammatory event, reactive oxygen species accumulation and certain driver mutations, normal epithelial cells progress through different stages to build an adenocarcinoma.…”

“…These stages start with the build-up of prostatic intra-epithelial neoplasia, which then develops into an adenocarcinoma. The latter might become castration-insensitive and metastasizes, preferentially in bone (reviewed in [119]). Initiation and progression of prostate cancer are highly coupled with metabolic rearrangements.…”

“…In the past decades several drivers for prostate cancer and progression were identified at the genomic, transcriptional and protein-level [119,[173][174][175][176][177][178][179][180][181][182]. The acquisition of these driver mutations and subsequent tumor progression could either follow a linear pathway or a molecular diversity model as suggested by Rubin et al, 2011 [178].…”

Mapping mutations in prostate cancer exomes

“…Several common genetic abnormalities with clear roles in facilitating prostate cancer development and progression have been described previously. Copy number losses in the PTEN tumor suppressor are common across prostate cancers of broadranging severity, 3 while copy number gains in the androgen receptor (AR) are frequently observed and underscore the importance of the androgen signaling axis in both primary prostate cancer and CRPC. 3 As many as 75% of prostate cancers harbor a rearrangement involving the upstream regulatory elements of TMPRSS2 (an AR regulatory target) and the coding region of an ETS family transcription factor (e.g., TMPRSS2-ERG fusion gene), further demonstrating the essential nature of AR signaling in the expression of oncogenic gene targets driving prostate tumorigenesis.…”

“…Copy number losses in the PTEN tumor suppressor are common across prostate cancers of broadranging severity, 3 while copy number gains in the androgen receptor (AR) are frequently observed and underscore the importance of the androgen signaling axis in both primary prostate cancer and CRPC. 3 As many as 75% of prostate cancers harbor a rearrangement involving the upstream regulatory elements of TMPRSS2 (an AR regulatory target) and the coding region of an ETS family transcription factor (e.g., TMPRSS2-ERG fusion gene), further demonstrating the essential nature of AR signaling in the expression of oncogenic gene targets driving prostate tumorigenesis. 3,4 While these prototypical genetic aberrations including copy number changes and gene fusions reveal the mechanism of several growth and invasive strategies acquired by prostate cancers, less is known about the role of gene mutations in prostate tumorigenesis.…”